Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder, which occurs gradually, resulting in memory loss, behavior disturbances, personality changes and a decline in cognitive abilities; it is also the most common cause of dementia among the elderly. Neuropathological studies have demonstrated that cholinergic functions in the basal forebrain and cortex decline due to senile dementia during AD. While there are no successful treatments currently available to stop its degenerative progress, a promising therapeutic strategy for activating the cholinergic functions has been the use of cholinomimetic agents such as donepezil, galantamine, rivastigmine, tacrine, and memantine, each approved for human use by the FDA. With the exception of memantine, all are potent, reversible inhibitors of acetylcholinesterase (AChE; EC 3.1.1.7). Use of these drugs is limited in utility, however, due to adverse side-effects, such as hepatotoxicity, gastrointestinal disturbance, and problems with bioavailability. For this reason, research efforts aimed at improving the pharmacological profile of the prototypes continue.
AChE contains a narrow and deep active site gorge with two sites of ligand binding—an acylation site (or A-site) at the base of the gorge and a peripheral site (or P-site) near the gorge entrance. The P-site contributes to the catalytic efficiency of the enzyme by transiently binding substrates on their way to the acylation site, where a short-lived acyl enzyme intermediate is produced (Johnson et al., Biochem. 42:5438-5452 (2003)). The P-site, spanned by residues W286 (hAChE) near the mouth of the gorge and D74 (hAChE) near a constriction at the boundary between the P-site and the A-site, specifically binds fluorescent probe Thioflavin T (De Ferrari et al., J. Biol. Chem. 276: 23282-23287 (2001)). Thioflavin T, a benzothiazole-based fluorophore widely used to detect amyloid structure in proteins, binds selectively to the AChE P-site with an equilibrium dissociation constant of 1.0 μM. Donepezil (donepezil hydrochloride, trade name: Aricept®, E2020, CAS #120014-06-4, 2-(1-benzyl-piperidin-4-ylmethyl)-5,6-dimethoxy-indan-1-one), is an acetylcholinesterase inhibitor with IC50 of 15 nM (hAChE), 26 nM (EeAChE) and 7273 nM (BuChE) (Hyatt et al., Chem. Biol. Interact. 157-158:247-252 (2005); and Camps et al., J. Med. Chem. 51:3588-3598 (2008)). Thioflavin T appears to be a dual-site binding AChE inhibitor interacting with both A- and P-sites of AChE. New compound types capable of binding A- and P-sites incorporating thiazole heterocycles as a motif could improve selectivity toward AChE and thereby improve therapeutic utility against neurodegenerative diseases and disorders.
The primary molecular target of organophospate nerve agents, whether weaponized or used as insecticides, is AChE. As nerve agents may inhibit other enzymes and because the receptors for acetylcholine (muscarinic and nicotinic acetylcholine receptors) are widely expressed, these agents can impact a number of biological processes. In addition to well-known CNS effects, vascular and inflammatory effects of nerve agents include vasoconstriction, an increase in blood brain barrier permeability, as well as modulation of lymphocyte proliferation and cytokine production. Exposure to organophosphates used in weapons or insecticides can result in significant morbidity or death. Present treatment of organophosphate poisoning consists of post-exposure intravenous or intramuscular administration of various combinations of drugs, including carbamates (e.g., pyridostigmine), anti-muscarinics (e.g., atropine), and ChE-reactivators such pralidoxime chloride (2-PAM). Novel inhibitors of AChE that block the binding of organophosphates can be used as prophylactic treatments for patients (e.g., a human, such as soldier or farmer) at risk for exposure to an organophosphate insecticide or chemical agent.
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